The mission of the Developmental Biology and Pathology Center (DBPC) in the PASS Network is to conduct human research into the biological aspects of alcohol-related injury as they relate to stillbirth, sudden infant death syndrome (SIDS), and fetal alcohol spectrum disorders (FASD). The four Specific Aims of the DPBC are: Placenta-To determine the role of maternal alcohol exposure, as potentially modified by other environmental factors, in placental dysfunction and pathology;Brainstem-To determine the role of prenatal alcohol, as potentially modified by other environmental factors, in neurotransmitter brainstem pathology in SIDS and stillbirth;Cerebral Cortex-^To determine the effects of prenatal alcohol exposure, as potentially modified by other environmental factors, on the neurotransmitter and synaptic development of the cerebral cortex In the fetus and infant in neural networks that mediate cognitive functions known to be abnormal In FASD;and Genetics-^To determine the role of copy number variants in modifying the risk for SIDS, stillbirth, and FASD associated with prenatal alcohol exposure. In addition to alcohol-related research in human tissues, the DBPC's mission includes: 1) the supervision of a centralized tissue bank for placental, brain, and DNA research in the study, as well as for all future tissue-related studies 2) the determination of the cause of the fetal and infant deaths with the Pathology Subcommittee for all study purposes. As requested in the RFA, we present here: 1) our progress in specimen management, training and consultation in pathology protocols, and process of case review and classification (DBPC infrastructure);and 2) our progress and plans for the placental, developmental brain, and genetic analyses (Specific Aims). The proposed study is significant because it has the potential to answer important clinical questions, is prenatal alcohol exposure toxic to the brainstem homeostatic (serotonergic) systems in the brainstem of SIDS infants? Do genetic copy number variants modify the effects of prenatal alcohol toxicity? The answers to these and other key questions will help shape future directions in risk reduction messages and predictors for SIDS, stillbirth causation, and cognitive assessment of infants exposed to prenatal alcohol. The proposed study is also innovative because it directly links pathological information in the human placenta and developing brain with in-depth information on prenatal exposure collected prospectively in a large, well-characterized cohort. The potential impact of this study is to help establish the biologic underpinnings of prenatal alcohol toxicity directly in the human placenta and developing brain as the basis for improved intervention strategies. PUBLIC HEALTH RELEVANCE: The mission of the Developmental Biology and Pathology Center is to conduct research into alcohol-related injury as it relates to stillbirth, sudden infant death syndrome (SIDS), and fetal alcohol spectrum disorders (FASD)-all major public health problems worldwide. This study will help establish the mechanisms of prenatal alcohol toxicity in the human placenta and developing brain as a critical step towards improved intervention.